PRODUCT MONOGRAPH - Sandoz Canada · Sandoz Losartan may be used alone or concomitantly with thiazide diuretics. A great majority of patients with severe hypertension in controlled

Sandoz Losartan Page 1 of 38

PRODUCT MONOGRAPH

Pr SANDOZ LOSARTAN

Losartan Potassium Tablets

25, 50 and 100 mg Tablets

Angiotensin II Receptor Antagonist

Sandoz Canada Inc. Date of Revision: November 13, 2018

110 Rue de Lauzon

Boucherville, QC, Canada

J4B 1E6

Submission Control No: 221716


Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION ........................................................................................ 3

SUMMARY PRODUCT INFORMATION .............................................................................................................. 3 INDICATIONS AND CLINICAL USE .................................................................................................................... 3 CONTRAINDICATIONS ......................................................................................................................................... 4 WARNINGS AND PRECAUTIONS ........................................................................................................................ 4 DRUG INTERACTIONS ........................................................................................................................................ 10 DOSAGE AND ADMINISTRATION .................................................................................................................... 12 OVERDOSAGE ...................................................................................................................................................... 14 ACTION AND CLINICAL PHARMACOLOGY ................................................................................................... 14 STORAGE AND STABILITY ................................................................................................................................ 17 DOSAGE FORMS, COMPOSITION AND PACKAGING .................................................................................... 17

PART II: SCIENTIFIC INFORMATION .............................................................................................................. 19

PHARMACEUTICAL INFORMATION ............................................................................................................... 19 CLINICAL TRIALS ............................................................................................................................................... 20 DETAILED PHARMACOLOGY ........................................................................................................................... 29 TOXICOLOGY ....................................................................................................................................................... 29 REFERENCES ........................................................................................................................................................ 34

PART III: CONSUMER INFORMATION ............................................................................................................. 36


Pr SANDOZ LOSARTAN


PART I: HEALTH PROFESSIONAL INFORMATION

SUMMARY PRODUCT INFORMATION

Route of

Administration

Dosage Form/

Strength

Nonmedicinal Ingredients

Oral Tablet 25 mg, 50 mg,

100 mg

Colloidal anhydrous silica, hydroxypropyl

cellulose, hypromellose, lactose monohydrate,

macrogol 400, magnesium stearate,

microcrystalline cellulose, pregelatinized

starch, talc and colouring agents (titanium

dioxide).

INDICATIONS AND CLINICAL USE

Hypertension: Sandoz Losartan (losartan potassium) is indicated for the treatment of essential

hypertension. Sandoz Losartan is also indicated in patients with essential hypertension and left

ventricular hypertrophy (see CLINICAL TRIALS).

Sandoz Losartan may be used alone or concomitantly with thiazide diuretics.

A great majority of patients with severe hypertension in controlled clinical trials required

combination therapy. Losartan potassium has been used concomitantly with beta-blockers and

calcium channel blockers, but the data on such use are limited.

Type 2 Diabetic Patients with Proteinuria and Hypertension: Sandoz Losartan is also

indicated to delay the progression of renal disease as measured by the occurrence of doubling of

serum creatinine, and end stage renal disease, and to reduce proteinuria (see CLINICAL

TRIALS).

Geriatrics (≥ 65 years of age): In clinical studies, there was no age-related difference in the

efficacy or safety profile of losartan (see WARNINGS AND PRECAUTIONS).

Pediatrics (6-16 years of age): Antihypertensive effects of losartan potassium have been

demonstrated in hypertensive pediatric patients aged 6 to 16 years. Use of losartan potassium in

these age groups is supported by evidence from adequate and well-controlled studies of losartan

potassium in pediatric patients (see CONTRAINDICATIONS, WARNINGS AND

PRECAUTIONS, ACTION AND CLINICAL PHARMACOLOGY and CLINICAL TRIALS).


CONTRAINDICATIONS

Patients who are hypersensitive to this drug or to any ingredient in the formulation or

component of the container. For a complete listing, see DOSAGE FORMS,

COMPOSITION AND PACKAGING section of the Product Monograph.

Concomitant use of angiotensin receptor antagonists (ARBs) –including losartan - or of

angiotensin-converting-enzyme inhibitors (ACEIs) with aliskiren-containing drugs in

patients with diabetes mellitus (type 1 or type 2) or moderate to severe renal impairment

(GFR < 60 ml/min/1.73 m2) is contraindicated (see WARNINGS and PRECAUTIONS,

Dual Blockade of the Renin-Angiotensin System (RAS) and Renal, and DRUG

INTERACTIONS, Dual Blockade of the Renin-Angiotensin-System (RAS) with ACEIs,

ARBs or aliskiren-containing drugs).

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

When used in pregnancy, angiotensin receptor (AT1) blockers (ARB) can cause

injury or even death of the developing fetus. When pregnancy is detected, Sandoz

Losartan should be discontinued as soon as possible (see WARNINGS AND

PRECAUTIONS, Special Populations).

Carcinogenesis and Mutagenesis

There is no evidence of carcinogenesis and mutagenesis associated with losartan (see

TOXICOLOGY).

Cardiovascular

Hypotension: Occasionally, symptomatic hypotension has occurred after administration of

losartan, in some cases after the first dose. It is more likely to occur in patients who are volume-

depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. In these

patients, because of the potential fall in blood pressure, therapy should be started under close

medical supervision. Similar considerations apply to patients with ischemic heart or

cerebrovascular disease, in whom an excessive fall in blood pressure could result in myocardial

infarction or cerebrovascular accident.

Valvular Stenosis: There is concern on theoretical grounds that patients with aortic stenosis

might be at particular risk of decreased coronary perfusion when treated with vasodilators

because they do not develop as much afterload reduction.

Dual blockade of the Renin-Angiotensin System (RAS)

There is evidence that co-administration of angiotensin receptor antagonists (ARBs), such as

losartan, or of angiotensin-converting-enzyme inhibitors (ACEIs) with aliskiren increases the

risk of hypotension, syncope, stroke, hyperkalemia and deterioration of renal function, including

renal failure, in patients with diabetes mellitus (type 1 or type 2) and/or moderate to severe renal

impairment (GFR < 60 ml/min/1.73 m2). Therefore, the use of losartan in combination with

aliskiren-containing drugs is contraindicated in these patients. Co-administration of ARBs,


including losartan, with other agents blocking the RAS, such as ARBs or aliskiren-containing

drugs, is not recommended in any patients, as adverse outcomes cannot be excluded.

Hepatic/Biliary/Pancreatic

Hepatic Impairment: Based on pharmacokinetic data which demonstrate significantly increased

plasma concentrations of losartan and its active metabolite in cirrhotic patients after

administration of losartan potassium, a lower dose should be considered for patients with hepatic

impairment, or a history of hepatic impairment (see DOSAGE AND ADMINISTRATION and

DETAILED PHARMACOLOGY).

Renal

Renal Impairment: As a consequence of inhibiting the renin-angiotensin-aldosterone system,

changes in renal function have been reported in susceptible individuals. In patients whose renal

function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients

with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe

congestive heart failure, treatment with agents that inhibit this system has been associated with

oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible

patients, concomitant diuretic use may further increase risk.

The use of ARBs – including losartan – or of ACEIs with aliskiren-containing drugs is

contraindicated in patients with moderate to severe renal impairment (GFR <60 ml/min/1.73 m2).

(See CONTRAINDICATIONS and DRUG INTERACTIONS, Dual Blockade of the Renin-

Angiotensin-System (RAS) with ARBs, ACEIs, or aliskiren-containing drugs).

Use of losartan should include appropriate assessment of renal function.

Hyperkalemia: In a clinical study conducted in patients with type 2 diabetes with proteinuria

and hypertension, the incidence of hyperkalemia was higher in the group treated with losartan

potassium (9.9%) as compared to the placebo group (3.4%), however, few patients discontinued

therapy due to hyperkalemia. Careful monitoring of serum potassium is recommended (see

CLINICAL TRIALS and ADVERSE REACTIONS, Abnormal Hematologic and Clinical

Chemistry Findings).

Concomitant use of other drugs that may increase serum potassium may lead to hyperkalemia

(see DRUG INTERACTIONS)

Sensitivity/Resistance

Hypersensitivity: Anaphylactic reactions, angioedema (involving swelling of the larynx and

glottis causing airway obstruction and/or swelling of the face, lips, and/or tongue and pharynx,

requiring intubation/tracheotomy in some cases) have been reported rarely in patients treated

with losartan; some of these patients previously experienced angioedema with ACE inhibitors.

Vasculitis, including Henoch-Schoenlein purpura, has been reported rarely.

Special Populations

Pregnant Women: Drugs that act directly on the renin-angiotensin-aldosterone-system (RAAS)

can cause fetal and neonatal morbidity and death when administered to pregnant women. When

pregnancy is detected, Sandoz Losartan should be discontinued as soon as possible.


The use of ARB is not recommended during pregnancy. Epidemiological evidence regarding the

risk of teratogenicity following exposure to angiotensin converting enzyme inhibitors (another

class of therapeutic products interfering with the RAAS) during the first trimester of pregnancy

has not been conclusive; however a small increase in risk cannot be excluded. Given the current

evidence available on the risk with ARB, similar risks may exist for this class of drugs. Patients

planning pregnancy should be changed to alternative anti-hypertensive treatments which have an

established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with

angiotensin II antagonists should be stopped immediately, and, if appropriate, alternative therapy

should be started.

The use of ARBs during the second and third trimesters is known to induce human fetotoxicity

(decreased renal function; oligohydramnios, skull ossification retardation) and neonatal toxicity

(renal failure, hypotension, hyperkalemia).

Infants with a history of in utero exposure to ARBs should be closely observed for hypotension,

oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of

blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means

of reversing hypotension and/or substituting for impaired renal function; however, limited

experience with those procedures has not been associated with significant clinical benefit.

Neither losartan nor the active metabolite can be removed by hemodialysis.

Animal data

Losartan potassium has been shown to produce adverse effects in rat fetuses and neonates, which

include decreased body weight, mortality and/or renal toxicity. Significant levels of losartan and

its active metabolite were shown to be present in rat milk. Based on pharmacokinetic

assessments, these findings are attributed to drug exposure in late gestation and during lactation.

Nursing Women: It is not known whether losartan or its active metabolite are excreted in

human milk, but significant levels of both of these compounds have been found in the milk of

lactating rats. Because many drugs are excreted in human milk, and because of their potential for

affecting the nursing infant adversely, a decision should be made whether to discontinue nursing

or discontinue the drug, taking into account the importance of the drug to the mother.

Geriatrics (≥ 65 years of age): No overall differences in safety were observed between elderly

and younger patients, but appropriate caution should nevertheless be used when prescribing to

elderly, as increased vulnerability to drug effect is possible in this patient population. This

conclusion is based on 391 of 2085 (19%) patients, 65 years and over who received losartan

monotherapy in controlled trials for hypertension. This was also the finding in a controlled

clinical study in type 2 diabetic patients with proteinuria and hypertension with 248 (33%) of

patients 65 years of age and over and in a controlled clinical study in hypertensive patients with

left ventricular hypertrophy with 2857 (62%) of patients 65 years of age and over (see

CLINICAL TRIALS).

Pediatrics: The antihypertensive effect has been demonstrated in a dose-response study of a

limited duration of three weeks, after which half of the patients continued on assigned dosage up

to six weeks. Blood pressure declines were maintained in the two highest dose groups.


Renal Impairment

There are no data on the effect of losartan potassium on blood pressure in pediatric patients

under the age of six years and neonate, or in pediatric patients with glomerular filtration rate

<30 mL/min/1.73 m2.

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal

function have been reported in susceptible individuals. In patients whose renal function may

depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral

renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive

heart failure, treatment with agents that inhibit this system has been associated with oliguria,

progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients,

concomitant diuretic use may further increase risk.

Use of losartan should include appropriate assessment of renal function.

Hepatic Impairment

There are no data on the effect of losartan potassium in pediatric patients with hepatic

impairments. Long-term safety has been studied in pediatric patients, as an extension of

6 months of the above cited dose-response study.

The pharmacokinetics of losartan have been investigated in 50 hypertensive pediatric patients

>1 month to <16 years of age following once daily oral administration of approximately 0.54 to

0.77 mg/kg of losartan (mean doses). The active metabolite is formed from losartan in all age

groups. Pharmacokinetics of losartan and its active metabolite are generally similar across the

studied age groups and consistent with pharmacokinetic historic data in adults (see ADVERSE

REACTIONS and CLINICAL TRIALS).

Race: In the LIFE study, Afro-American Black patients treated with atenolol were at lower risk

of experiencing the primary composite endpoint and stroke compared with Afro-American Black

patients treated with losartan potassium. Based on the LIFE study, the benefits of losartan

potassium on the primary composite endpoint and stroke compared to atenolol do not apply to

Afro-American Black patients with hypertension and left ventricular hypertrophy although both

treatment regimens effectively lowered blood pressure in these patients (see CLINICAL

TRIALS).

Monitoring and Laboratory Tests

Not applicable.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

Losartan potassium has been evaluated for safety in more than 3300 patients treated for essential

hypertension. Of these, 2085 were treated with losartan monotherapy in controlled clinical trials.


In open studies, over 1200 patients were treated with losartan for more than 6 months, and over

800 for more than one year.

In controlled clinical trials, discontinuation of therapy due to clinical adverse experiences

occurred in 2.3% and 3.7% of patients treated with losartan potassium and placebo, respectively.

The following potentially serious adverse reactions have been reported rarely with losartan in

controlled clinical trials: syncope, hypotension.

No relevant differences between the adverse experience profile for pediatric patients and the

previously reported for adult patients were identified.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction

rates observed in the clinical trials may not reflect the rates observed in practice and

should not be compared to the rates in the clinical trials of another drug. Adverse drug

reaction information from clinical trials is useful for identifying drug-related adverse

events and for approximating rates.

In these double-blind controlled clinical trials, the following adverse reactions reported with

losartan occurred in ≥1 % of patients, regardless of drug relationship:

Losartan

(n=2085)

Placebo

(n=535)

Body as a Whole

Asthenia/fatigue

Edema/swelling

Abdominal pain

Chest pain

3.8

1.7

1.7

1.1

3.9

1.9

1.7

2.6

Cardiovascular

Palpitation

Tachycardia

1.0

1.0

0.4

1.7

Digestive

Diarrhea

Dyspepsia

Nausea

1.9

1.1

1.8

1.9

1.5

2.8

Musculoskeletal

Back pain

Muscle cramps

1.6

1.0

1.1

1.1

Nervous/Psychiatric

Dizziness

Headache

4.1

14.1

2.4

17.2


Losartan

(n=2085)

Placebo

(n=535)

Insomnia

1.1

0.7

Respiratory

Cough

Nasal congestion

Pharyngitis

Sinus disorder

Upper respiratory infection

3.1

1.3

1.5

1.0

6.5

2.6

1.1

2.6

1.3

5.6

In these controlled clinical trials for essential hypertension, dizziness was the only adverse

experience, occurring in more than 1% of cases, that was reported as drug-related, and that

occurred at a greater incidence in losartan-treated (2.4%) than placebo-treated (1.3%) patients.

Losartan potassium was generally well tolerated in a controlled clinical trial in type 2 diabetic

patients with proteinuria and hypertension. The most common drug-related side effects were

asthenia/fatigue, dizziness, hypotension and hyperkalemia (See WARNINGS AND

PRECAUTIONS). In hypertensive patients with left ventricular hypertrophy, the most common

drug-related side effects were dizziness, asthenia/fatigue, and vertigo.

Less Common Clinical Trial Adverse Drug Reactions (<1%)

In double-blind, controlled clinical trials for essential hypertension, the following adverse

reactions were reported with losartan potassium at an occurrence rate of less than 1%, regardless

of drug relationship: orthostatic effects, somnolence, vertigo, epistaxis, tinnitus, constipation,

malaise, rash.

Abnormal Hematologic and Clinical Chemistry Findings

In controlled clinical trials for essential hypertension, clinically important changes in standard

laboratory parameters were rarely associated with administration of losartan potassium.

Liver Function Tests: In double-blind hypertensive trials, elevations of AST and ALT occurred

in 1.1% and 1.9% of patients treated with losartan monotherapy and in 0.8% and 1.3% of

patients treated with placebo, respectively. When AST or ALT elevations ≥2X upper limit of

normal were compared, the frequency was similar to that seen in placebo.

Hyperkalemia: In controlled clinical trials for essential hypertension, hyperkalemia (serum

potassium >5.5 mEq/L) occurred in 1.5% of patients treated with losartan potassium.

In a clinical study conducted in type 2 diabetic patients with proteinuria and hypertension, 9.9%

of patients treated with losartan potassium and 3.4% of patients treated with placebo developed

hyperkalemia (see WARNINGS AND PRECAUTIONS, Renal, Hyperkalemia).

Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen (BUN) or serum

creatinine were observed in less than 0.1 percent of patients with essential hypertension treated

with losartan potassium alone. No patient discontinued taking losartan potassium alone due to

increased BUN or serum creatinine.


Hemoglobin and Hematocrit: Small decreases in hemoglobin and hematocrit (mean decreases

of approximately 0.11 gram percent and 0.09 volume percent, respectively) occurred frequently

in patients treated with losartan potassium alone, but were rarely of clinical importance. In

controlled clinical trials no patients were discontinued due to anemia. Discontinuation of losartan

treatment due to anemia was reported with post-marketing use of losartan.

In clinical trials, the following were noted to occur with an incidence of <1%, regardless of drug

relationship: thrombocytopenia, eosinophilia.

Post-Market Adverse Drug Reactions

Other adverse reactions reported rarely in open-label studies or post-marketing use in patients

with essential hypertension, regardless of drug relationship, include anemia, thrombocytopenia

(reported rarely), hepatitis, liver function tests abnormalities, vomiting, drug induced cough,

asthenia, diarrhea, migraine, dysgeusia, arthralgia, pruritus, erythroderma, taste disorder,

urticaria malaise, erectile dysfunction/impotence and photosensitivity. Cases of muscle pain,

muscle weakness, myositis and rhabdomyolysis have been reported in patients receiving

angiotensin II receptor blockers.

Anaphylactic reactions, angioedema (involving swelling of the larynx and glottis causing airway

obstruction and/or swelling of the face, lips, and/or tongue and pharynx, requiring

intubation/tracheotomy in some cases) have been reported rarely in patients treated with losartan;

some of these patients previously experienced angioedema with ACE inhibitors. Vasculitis,

including Henoch-Schoenlein purpura, has been reported rarely.

DRUG INTERACTIONS

Drug-Drug Interactions

Diuretics: Patients on diuretics, and especially those in whom diuretic therapy was recently

instituted, may occasionally experience an excessive reduction of blood pressure after initiation

of therapy with losartan potassium. The possibility of symptomatic hypotension with the use of

losartan potassium can be minimized by discontinuing the diuretic prior to initiation of treatment

and/or lowering the initial dose of losartan (see WARNINGS AND PRECAUTIONS,

Cardiovascular, Hypotension and DOSAGE AND ADMINISTRATION). No drug interaction of

clinical significance has been identified with thiazide diuretics.

Agents Increasing Serum Potassium: Concomitant use of potassium-sparing diuretics (e.g.

spironolactone, triamterene, amiloride), potassium supplements, salt substitutes containing

potassium, or other drugs that may increase serum potassium (e.g., trimethoprim-containing

products) may lead to increases in serum potassium.

Since losartan potassium decreases the production of aldosterone, potassium-sparing diuretics or

potassium supplements should be given only for documented hypokalemia and with frequent

monitoring of serum potassium. Potassium-containing salt substitutes should also be used with

caution.


Dual Blockade of the Renin-Angiotensin-System (RAS) with ARBs, ACEIs or aliskiren

containing drugs: Dual Blockade of the Renin-Angiotensin-System (RAS) with ARBs, ACEIs

or aliskiren-containing drugs is contraindicated in patients with diabetes and/or renal impairment,

and is not recommended in any other patients, as adverse outcomes cannot be excluded. See

CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Dual Blockade of the

Renin-Angiotensin-System (RAS).

Lithium Salts: As with other drugs which affect the excretion of sodium, lithium excretion may

be reduced. Therefore, serum lithium levels should be monitored carefully if lithium salts are to

be coadministered with angiotensin II receptor antagonists.

Digitalis: In 9 healthy volunteers, when a single oral dose of 0.5 mg digoxin was administered to

patients receiving losartan for 11 days, digoxin AUC and digoxin Cmax ratios, relative to placebo,

were found to be 1.06 (90% C.I. 0.98 - 1.14) and 1.12 (90% C.I. 0.97 - 1.28), respectively. The

effect of losartan on steady state-pharmacokinetics of cardiac glycosides is not known.

Warfarin: Losartan administered for 7 days did not affect the pharmacokinetics or

pharmacodynamic activity of a single dose of warfarin. The effect of losartan on steady-state

pharmacokinetics of warfarin is not known.

Drugs Affecting Cytochrome P450 System: Rifampin, an inducer of drug metabolism,

decreases the concentrations of the active metabolite of losartan. In humans, two inhibitors of

P450 3A4 have been studied. Ketoconazole did not affect the conversion of losartan to the active

metabolite after intravenous administration of losartan, and erythromycin had no clinically

significant effect after oral losartan administration. Fluconazole, an inhibitor of P450 2C9,

decreased active metabolite concentration. The pharmacodynamic consequences of concomitant

use of losartan and inhibitors of P450 2C9 have not been examined.

When losartan was administered to 10 healthy male volunteers as a single dose in steady-state

conditions of phenobarbital, a cytochrome P450 inducer, losartan AUC, relative to baseline, was

0.80 (90% C.I. 0.72 - 0.88), while AUC of the active metabolite, E-3174, was 0.80 (90% C.I.

0.78 - 0.82).

When losartan was administered to 8 healthy male volunteers as a single dose in steady-state

conditions of cimetidine, a cytochrome P450 inhibitor, losartan AUC, relative to baseline, was

1.18 (90% C.I. 1.10 - 1.27), while AUC of the active metabolite, E-3174, was 1.00 (90% C.I.

0.92 - 1.08).

Non-Steroidal Anti-Inflammatory Drugs Including Cyclooxygenase-2 Inhibitors: Non-

steroidal anti-inflammatory drugs (NSAIDs) including indomethacin and selective

cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of diuretics and other

antihypertensive drugs. Therefore, the antihypertensive effect of angiotensin II receptor

antagonists or ACE inhibitors may be attenuated by NSAIDs including selective COX-2

inhibitors.


In some patients with compromised renal function (e.g., elderly patients or patients who are

volume-depleted, including those on diuretic therapy) who are being treated with NSAIDS,

including selective COX-2 inhibitors, the coadministration of angiotensin II receptor antagonists

or ACE inhibitors may result in a further deterioration of renal function. Cases of acute renal

failure, usually reversible, have been reported. Therefore, this combination should be

administered with caution in this patient population.

Drug-Food Interactions

Losartan potassium may be administered with or without food.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

Sandoz Losartan may be administered with or without food, however it should be taken

consistently with respect to food intake at about the same time every day.

Hypertension: The dosage of Sandoz Losartan must be individualized.

Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent

of blood pressure elevation, salt restriction, and other pertinent clinical factors. The dosage of

other antihypertensive agents used with Sandoz Losartan may need to be adjusted.

Monotherapy: The usual starting dose of Sandoz Losartan is 50 mg once daily.

Dosage should be adjusted according to blood pressure response. The maximal antihypertensive

effect is attained 3-6 weeks after initiation of therapy.

The usual dose range for Sandoz Losartan is 50 to 100 mg once daily. A dose of 100 mg daily

should not be exceeded, as no additional antihypertensive effect is obtained with higher doses.

In most patients taking Sandoz Losartan 50 mg once daily, the antihypertensive effect is

maintained. In some patients treated once daily, the antihypertensive effect may diminish toward

the end of the dosing interval. This can be evaluated by measuring the blood pressure just prior

to dosing to determine whether satisfactory control is being maintained for 24 hours. If it is not,

either twice daily administration with the same total daily dosage, or an increase in the dose

should be considered. If blood pressure is not adequately controlled with Sandoz Losartan alone,

a non-potassium-sparing diuretic may be administered concomitantly.


For patients with volume-depletion, a starting dose of 25 mg once daily should be considered

(see WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension and DRUG

INTERACTIONS).

Concomitant Diuretic Therapy: In patients receiving diuretics, Sandoz Losartan therapy

should be initiated with caution, since these patients may be volume-depleted and thus more

likely to experience hypotension following initiation of additional antihypertensive therapy.

Whenever possible, all diuretics should be discontinued two to three days prior to the

administration of Sandoz Losartan, to reduce the likelihood of hypotension (see WARNINGS

AND PRECAUTIONS, Cardiovascular, Hypotension and DRUG INTERACTIONS). If this is

not possible because of the patient’s condition, Sandoz Losartan should be administered with

caution and the blood pressure monitored closely. Thereafter, the dosage should be adjusted

according to the individual response of the patient.

Type 2 Diabetic Patients with Proteinuria and Hypertension: The usual starting dose is

50 mg once daily. The dose may be increased to 100 mg once daily based on blood pressure

response. Sandoz Losartan may be administered with other antihypertensive agents (e.g.

diuretics, calcium channel blockers, alpha- or beta-blockers, and centrally acting agents) as well

as with insulin and other commonly used hypoglycemic agents (e.g. sulfonylureas, glitazones

and glucosidase inhibitors).

Geriatrics (≥ 65 years of age): No initial dosage adjustment is necessary for most elderly

patients. However, appropriate monitoring of these patients is recommended.

Pediatrics (6-16 years of age): For patients who can swallow tablets, the recommended dose is

25 mg once daily in patients ≥20 to <50 kg. The dose can be increased to a maximum of 50 mg

once daily. In patients ≥50 kg, the starting dose is 50 mg once daily. The dose can be increased

to a maximum of 100 mg once daily.

Dosage should be adjusted to blood pressure response.

In pediatric patients who are intravascularly volume depleted, these conditions should be

corrected prior to administration of Sandoz Losartan.

Sandoz Losartan is not recommended in pediatric patients with glomerular filtration rate

<30 mL/min/1.73 m2, in pediatric patients with hepatic impairment, or in neonates as no data are

available.

Renal Impairment: No initial dosage adjustment is usually necessary for patients with renal

impairment, including those requiring hemodialysis. However, appropriate monitoring of these

patients is recommended.

Hepatic Impairment: An initial dosage of 25 mg should be considered for patients with hepatic

impairment, or a history of hepatic impairment (see WARNINGS AND PRECAUTIONS,

Hepatic/Biliary/Pancreatic, Hepatic Impairment and DETAILED PHARMACOLOGY).


Missed Dose

If a dose is missed, an extra dose should not be taken. The usual schedule must be resumed.

OVERDOSAGE

Limited data are available in regard to overdosage with losartan potassium in humans. The most

likely manifestation of overdosage would be hypotension and/or tachycardia. If symptomatic

hypotension should occur, supportive treatment should be instituted.

Neither losartan nor the active metabolite can be removed by hemodialysis.

For management of a suspected drug overdose, contact your regional Poison Control Centre.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Losartan potassium antagonizes angiotensin II by blocking the angiotensin type one (AT1)

receptor.

Angiotensin II is the primary vasoactive hormone of the renin-angiotensin system. Its effects

include vasoconstriction and the stimulation of aldosterone secretion by the adrenal cortex.

Losartan, and its active metabolite, E-3174, block the vasoconstrictor and aldosterone-secreting

effects of angiotensin II by selectively blocking the binding of angiotensin II to AT1 receptors

found in many tissues, including vascular smooth muscle. A second type of angiotensin II

receptor has been identified as the AT2 receptor, but it plays no known role in cardiovascular

homeostasis to date. Both losartan and its active metabolite do not exhibit any agonist activity at

the AT1 receptor, and have much greater affinity, in the order of 1000-fold, for the AT1 receptor

than for the AT2 receptor. In vitro binding studies indicate that losartan itself is a reversible,

competitive antagonist at the AT1 receptor, while the active metabolite is 10 to 40 times more

potent than losartan, and is a reversible, non-competitive antagonist of the AT1 receptor.

Neither losartan nor its active metabolite inhibits angiotensin converting enzyme (ACE), also

known as kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades

bradykinin, nor do they bind to or block other hormone receptors or ion channels known to be

important in cardiovascular regulation.

Pharmacodynamics

Losartan inhibits the pressor effect of angiotensin II. A dose of 100 mg inhibits this effect by

about 85% at peak, with 25-40% inhibition persisting for 24 hours. Removal of the negative

feedback of angiotensin II causes a 2-3 fold rise in plasma renin activity, and a consequent rise in

angiotensin II plasma concentration, in hypertensive patients.

Maximum blood pressure lowering, following oral administration of a single dose of losartan, as

seen in hypertensive patients, occurs at about 6 hours.


In losartan-treated patients during controlled trials, there was no meaningful change in heart rate.

There is no apparent rebound effect after abrupt withdrawal of losartan therapy.

Black hypertensive patients show a smaller average blood pressure response to losartan

monotherapy than other hypertensive patients.

Pharmacokinetics Table 1: Pharmacokinetic Parameters in Hypertensive Adults Following Multiple Dosing

Adults given 50 mg once daily for 7 days

n=12

Parent Active Metabolite

AUC0-24 hra(ng·hr/mL) 442 ± 173 1685 ± 452

Cmax (ng/mL)a 224 ± 82 212 ± 73

T½ (h)b 2.1 ± 0.70 7.4 ± 2.4

Tmax (h)c 0.9 3.5

CLr (mL/min) a 56 ± 23 20 ± 3 a Mean ± standard deviation

b Harmonic mean ± standard deviation

c Median

Absorption: Following oral administration, losartan is well absorbed, with systemic

bioavailability of losartan approximately 33%. About 14% of an orally-administered dose of

losartan is converted to the active metabolite, although about 1% of subjects did not convert

losartan efficiently to the active metabolite.

Mean peak concentrations of losartan occur at about one hour, and that of its active metabolite at

about 3-4 hours. Although maximum plasma concentrations of losartan and its active metabolite

are approximately equal, the AUC of the metabolite is about 4 times greater than that of losartan.

Distribution: Both losartan and its active metabolite are highly bound to plasma proteins,

primarily albumin, with plasma free fractions of 1.3% and 0.2% respectively. Plasma protein

binding is constant over the concentration range achieved with recommended doses. Studies in

rats indicate that losartan crosses the blood-brain barrier poorly, if at all.

The volume of distribution of losartan is about 34 litres, and that of the active metabolite is about

12 litres.

Metabolism: Losartan is an orally active agent that undergoes substantial first-pass metabolism

by cytochrome P450 enzymes. It is converted, in part, to an active carboxylic acid metabolite,

E-3174, that is responsible for most of the angiotensin II receptor antagonism that follows oral

losartan administration.

Various losartan metabolites have been identified in human plasma and urine. In addition to the

active carboxylic acid metabolite, E-3174, several inactive metabolites are formed. In vitro


studies indicate that the cytochrome P450 isoenzymes 2C9 and 3A4 are involved in the

biotransformation of losartan to its metabolites.

Excretion: The terminal half-life of losartan itself is about 2 hours, and that of the active

metabolite, about 6-9 hours. The pharmacokinetics of losartan and this metabolite are linear with

oral losartan doses up to 200 mg and do not change over time. Neither losartan nor its metabolite

accumulate in plasma upon repeated once-daily administration.

Total plasma clearance of losartan is about 600 mL/min, with about 75 mL/min accounted for by

renal clearance. Total plasma clearance of the active metabolite is about 50 mL/min, with about

25 mL/min accounted for by renal clearance. Both biliary and urinary excretion contribute

substantially to the elimination of losartan and its metabolites.

Following oral 14C-labeled losartan, about 35% of radioactivity is recovered in the urine and

about 60% in the feces. Following an intravenous dose of 14C-labeled losartan, about 45% of

radioactivity is recovered in the urine and 50% in the feces.

Pediatrics: The pharmacokinetics of losartan and its active metabolite were generally similar

across the studied age groups and historical pharmacokinetic data in adults.

Table 2: Pharmacokinetic Parameters in Hypertensive Infants and Toddlers (Group I: 3-23 months),

Preschool Children (Group II; 2-5 years), School-Age Children (Group III; 6-11 years), and Adolescents

(Group IV; 12-15 years) Following Multiple Dosing


AUC0-24 hr observed (ng·hr/mL)a

Group I (n=9) 244.5 ± 175.7 1456.5 ± 1422.7

Group II (n=12)† 314.5 ± 177.8 950.9 ± 498.0

Group III (n=11) 251.0 ± 265.6 1163.6 ± 1 017.5

Group IV (n=14) 303.1 ± 123.6 1589.9 ± 996.2

AUC0-24 hr per 0.7 mg/kga

Group I (n=9) 246.1 ± 154.0 1466.3 ± 1498.8

Group II (n=13) 305.2 ± 164.9 933.2 ± 510.5

Group III (n=11) 232.6 ± 199.4 1078.0 ± 783.4

Group IV (n=14) 405.4 ± 120.3 2126.8 ± 1082.4

Cmax observed (ng/mL)a

Group I (n=9) 66.6 ± 103.6 146.9 ± 179.5

Group II (n=12)† 89.8 ± 96.5 91.5 ± 75.2

Group III (n=11) 98.7 ± 94.5 139.1 ± 148.1

Group IV (n=14) 105.1 ± 112.3 188.2 ± 91.2

Cmax per 0.7 mg/kga

Group I (n=9) 67.0 ± 92.8 147.9 ± 190.6

Group II (n=13) 89.5 ± 88.3 92.0 ± 77.6

Group III (n=11) 91.4 ± 81.7 128.8 ± 112.1

Group IV (n=14) 140.6 ± 90.5 251.7 ± 118.2

T max (hr)c

Group I (n=9) 1.05 ± 1.38 5.53 ± 2.0

Group II (n=13) 1.07 ± 1.43 6.01 ± 1.5

Group III (n=11) 2.03 ± 1.79 4.46 ± 2.1

Group IV (n=14) 1.54 ± 1.27 5.00 ± 1.0



Half-Life (hr)b

Group I (n=9) 1.93 ± 0.44 4.83 ± 1.1

Group II (n=13) 2.37 ± 1.24 5.59 ± 1.1

Group III (n=11) 2.18 ± 1.50 5.37 ± 1.4

Group IV (n=14) 2.41 ± 1.84 5.72 ± 1.0 a Geometric Mean ± Standard Deviation b Harmonic Mean ± Standard Deviation c Median ± Standard Deviation † n=12: excludes AN 4051 who received 2.5 times the intended dose

A pharmacokinetic study was performed to estimate plasma and urine pharmacokinetic

parameters of losartan and its active metabolite, E-3174, in infants and toddlers, preschool

children, school-age children, and adolescents.

The pharmacokinetics of losartan and its active metabolite, E-3174, in this study were

comparable in all age groups studied. Differences in some parameters were statistically

significant, especially for the active metabolite, E-3174, when the preschool children were

compared with adolescents. Importantly, the youngest patients were comparable with older

pediatric patients, and the active metabolite, E-3174, was formed from losartan in all age groups

studied.

STORAGE AND STABILITY

Bottles: Store between 15 and 30°C. Keep container tightly closed. Protect from light.

Blisters: Store between 15 and 30°C.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Sandoz Losartan 25 mg tablets, are white, oval, unscored, film-coated tablets, debossed with

25 on one side. Available in bottles of 100 tablets.

Sandoz Losartan 50 mg tablets, are white, oval, unscored, film-coated tablets, debossed with

50 on one side. Available in bottles of 100 and 500 tablets and in blister packs of 30 tablets.

Sandoz Losartan 100 mg tablets, are white, teardrop-shaped, unscored, film-coated tablets,

debossed with 100 on one side. Available in bottles of 100 and 500 tablets and in blister packs of

30 tablets.

Sandoz Losartan is supplied as unscored film-coated tablets containing either25 mg, 50 mg, or

100 mg of the active ingredient, losartan potassium. Each tablet contains the following

nonmedicinal ingredients: colloidal anhydrous silica, hydroxypropyl cellulose, hypromellose,

lactose monohydrate, macrogol 400, magnesium stearate, microcrystalline cellulose,

pregelatinized starch, talc and colouring agent (titanium dioxide). Sandoz Losartan 25, 50 and


100 mg tablets contain the following amounts of potassium: 2.12 mg (<1 mmol), 4.24 mg

(<1 mmol), and 8.48 mg (<1 mmol) respectively.


PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Losartan potassium

Chemical name: 2-butyl-4-chloro-1-[[2’-(1H-tetrazol-5-yl)[1,1’-biphenyl]-4-

yl]methyl]- 1 H-imidazole-5-methanol monopotassium salt

Molecular formula: C22H22ClKN6O

Molecular mass: 461.01

Structural formula:

Physicochemical properties: Losartan potassium is a white to off-white free-flowing

crystalline powder. It is freely soluble in water, soluble in

alcohols, and slightly soluble in common organic solvents,

such as acetonitrile and methyl ethyl ketone.


CLINICAL TRIALS

A comparative, randomized, single-dose, 2-way, crossover bioavailability study of Sandoz

Losartan (losartan potassium) 100 mg Film-Coated Tablets (Sandoz Canada Inc.) and Cozaar®

(losartan potassium) (Merck Frosst Canada Ltd.) 100 mg tablets in 42 healthy adult males was

conducted under fasting conditions. Bioavailability data were measured and the results are

summarized in the following table.

Summary Table of the Comparative Bioavailability

Losartan

(1 x 100 mg tablet)

From measured data

Geometric Mean

(CV %)

N=42

Parameter Test* Reference† % Ratio of

Geometric Means

90% Confidence

Interval

AUCT

(ng x hr/mL)

697.28

(36.1%)

697.19

(38.4%)

100.0

97.5 – 102.5

AUCI

(ng x hr/mL)

711.03

(36.0%)

708.22

(37.9%)

99.7

97.2 – 102.2

Cmax

(ng/mL)

377.90

(61.3%)

387.52

(62.8%)

97.5

87.3 - 108.9

Tmax §

(hrs)

1.67 (64.2%) 1.68 (60.4%)

T½ §

(hrs)

2.16 (28.5%) 2.15 (28.5%)

* Sandoz Losartan (losartan potassium) 100 mg Film-Coated Tablets (manufactured for Sandoz Canada Inc.) † Cozaar® (losartan potassium) 100 mg tablets (Merck Frosst Canada Ltd.) § Expressed as the arithmetic mean (CV%) only.

Adult Hypertension

Study Demographics and Trial Design: Table 3: Summary of Patient Demographics for Double-Blind, Placebo-Controlled Clinical Trials in Adult

Patients with Hypertension

Study

No.

Trial Design Dosage, Route of Administration and

Duration

Study

Subjects

N=number

Mean

Age

(Range)

(Years)

Gender

(%)

011 Double-blind,

randomized,

parallel,

placebo-

Oral administration, once daily

Treatment groups:

576 53.1

(22-88)

Male: 66

Female: 34


Study

No.

Trial Design Dosage, Route of Administration and

Duration

Study

Subjects

N=number

Mean

Age

(Range)

(Years)

Gender

(%)

controlled Losartan 10, 25, 50, 100, 150 mg

Enalapril 20 mg and losartan placebo

Duration: 8 weeks double-blind therapy

021 Double-blind,

randomized,

parallel,

placebo-

controlled

Oral administration, once or twice daily

Treatment groups:

Losartan 50 mg once daily


Losartan 50 mg twice daily

Losartan placebo

Duration: 4 weeks double-blind

monotherapy

122 53.5

(28-76)

Male: 68

Female: 32

050 Double-blind,

randomized,

parallel,

placebo-

controlled


Treatment groups:

Placebo

Losartan 50 mg/placebo

Losartan 50 mg/losartan 100 mg

(possible titration to losartan 100 mg

after 6 weeks)


therapy

366 54

(26-78)

Male: 64

Female: 36

054 Double-blind,

randomized,

parallel,

placebo-

controlled


Treatment groups:

Placebo

Losartan 50 mg

HCTZ 12.5 mg

Losartan 50 mg/HCTZ 6.25 mg

Losartan 50 mg/HCTZ 12.5 mg


therapy

703 52.8

(21-79)

Male: 60

Female: 40

065 Double-blind,

randomized,

parallel,

placebo-

controlled

Oral administration, once or twice daily

Placebo



Losartan 25 mg twice daily


therapy

428 54

(24-79)

Male: 65

Female: 35


Study Results Table 4: Results of Losartan Efficacy Compared to Placebo in Double-Blind, Controlled Outpatient Trials

Study No. Treatment

(Dosage in mg)

Baseline Mean

DBP (S.D.)

mmHg

Adjusted Mean

DBP Change

Vs Placebo Efficacy

Parameter

(Duration)

011 Placebo 103.3 (3.8) -5.3 -- SuDBP

(8 weeks) Losartan 25 mg qd 103.3 (3.7) -6.4 NS

Losartan 50 mg qd 104.1 (3.7) -10.1 **

Losartan 100 mg qd 104.1 (4.3) -9.9 **

021 Placebo 100.3 (3.6) -2.1 -- SiDBP

(4 weeks) Losartan 50 mg qd 100.0 (4.6) -6.7 *

Losartan 100 mg qd 101.1 (4.8) -9.7 **

Losartan 50 mg bid 101.4 (4.7) -8.6 **

021 Placebo 94.8 (5.9) -0.8 -- ABPM 24 hr

Mean DBP

(4 weeks) Losartan 50 mg qd 94.0 (6.9) -5.6 **

Losartan 100 mg qd 93.8 (6.0) -7.1 **

Losartan 50 mg bid 94.4 (6.9) -9.0 **

050 Placebo 101.3 (4.9) -4.5 -- SiDBP


Losartan 50/100 mg bid 102.2 (5.0) -8.6 **

054 Placebo 101.3 (5.3) -4.0 -- SiDBP


065 Placebo 101.3 (5.1) -2.1 -- SiDBP


Losartan 50 mg qd 102.3 (6.3) -6.6 ** NS: Treatment difference not statistically significant

*: Treatment difference statistically significant, p≤0.05

**: Treatment difference statistically significant, p≤0.01

SiDBP: Sitting diastolic blood pressure

SuDBP: Supine diastolic blood pressure

ABPM: Ambulatory blood pressure monitoring

qd: Once daily

bid: Twice daily

The antihypertensive effects of losartan potassium were demonstrated principally in 5 placebo-

controlled, 6- to 12-week trials (study no. 011, 021, 050, 054, 065) of dosages from 10 to 150 mg

per day in patients with baseline diastolic blood pressures of 95-115. The studies allowed

comparisons of two doses (50-100 mg/day) as once-daily or twice-daily regimens, comparisons

of peak and trough effects, and comparisons of response by gender, age, and race.

Analysis of age, gender, and race subgroups of patients showed that men and women, and

patients over and under 65, had generally similar responses. The effect of losartan potassium was

somewhat less in Black patients (usually a low-renin population).

The effect of losartan is substantially present within one week but in some studies the maximal

effect occurred in 3-6 weeks.


RENAAL STUDY

Study Demographics and Trial Design Table 5: Summary of Patient Demographics for Clinical Trials

Study No. Trial Design Dosage, Route of

Administration

and Duration

Study

Subjects

(n=number)

Mean Age

(Range)

Gender

147 Double-blind,

randomized

placebo-controlled

(non-ACE inhibitor,

non AIIA

conventional

antihypertensives)

multinational study

Oral administration

Losartan 50 mg once

daily with titration to

losartan 100 mg

Matching placebo

Duration: 3.4 years

mean follow up

1513 60

(31 to 74 years)

Male: 956

(31 to 74 years)

Female: 557

(34 to 73 years)

Study Results Table 6: Results of RENAAL Study

End Point Losartan Group

(n=751)

Placebo Group

(n=762)

p-Value

Risk Reduction

% (95% CI)

No % No %

Primary Composite*

endpoint

327 (43.5) 359 (47.1) 0.022 16.1 (2 to 28)

Doubling of serum

creatinine concentration

162 (21.6) 198 (26.0) 0.006 25.3 (8 to 39)

End-stage renal disease 147 (19.6) 194 (25.5) 0.002 28.6 (11 to 42)

Death 158 (21.0) 155 (20.3) 0.884 -1.7 (-27 to 19)

* The primary endpoint was the time to first occurrence of any one of the following events: doubling of serum creatinine

concentration, end-stage renal disease (need for dialysis or transplantation) or death.

The Reduction of Endpoints in Non-Insulin Dependent Diabetes Mellitus (NIDDM) with the

Angiotensin II Receptor Antagonist Losartan (RENAAL) study was a large, multicenter,

randomized, placebo-controlled, double-blind study conducted worldwide in 1513 hypertensive

patients with type 2 diabetes and proteinuria [751 patients entered treatment with losartan

potassium]. The goal of the study was to demonstrate the renal protective effects of losartan

potassium over and above the benefits of blood pressure control alone. To meet this objective the

study was designed to achieve equal blood pressure control in both treatment groups. Patients

with proteinuria and serum creatinine of 1.3-3.0 mg/dL were randomized to receive losartan

potassium 50 mg once daily titrated according to blood pressure response, or placebo, on a

background of conventional antihypertensive therapy excluding ACE inhibitors and angiotensin

II antagonists. Investigators were instructed to titrate study drug to 100 mg once daily as

appropriate; 72% of patients were taking the 100 mg daily dose the majority of the time they

were on study drug. Other antihypertensive agents (diuretics, calcium-channel blockers, alpha- or

beta-blockers, and centrally-acting agents) could be added as needed in both groups. Patients

were followed for approximately 5 years (mean of 3.4 years).


Important inclusion criteria of the RENAAL study included: type 2 diabetes defined as : (1)

diabetes diagnosed after the age of 30; (2) insulin not required within the first 6 months of

diagnosis; and (3) no history of diabetic ketoacidosis; ages of 31 to 70; serum creatinine between

1.3 (1.5 for males >60 kg) and 3.0 mg/dL; and first morning urinary albumin/creatinine ratio

(UA/Cr) of ≥300 mg/g (or a 24-hour urine total protein of >500 mg/day). Patients could have

been normotensive or hypertensive.

Important exclusion criteria of the RENAAL study included: type 1 diabetes; history of heart

failure; history of myocardial infarction or coronary artery bypass graft surgery within 1 month

prior to study start, cerebral vascular accident or percutaneous transluminal coronary angioplasty

within 6 months prior to study start, and history of transient ischemic attacks (TIA) within the

year prior to study start; known history or current diagnosis of non-diabetic renal disease such as

chronic glomerulonephritis or polycystic kidney disease; and uncontrolled diabetes, i.e. HBA1c

>12%.

The primary endpoint of the study was the composite endpoint of doubling of serum creatinine,

end-stage renal disease (need for dialysis or transplantation), or death. The results showed that

treatment with losartan potassium (327 events, 43.5%) as compared with placebo (359 events,

47.1%) resulted in a 16.1% risk reduction (p=0.022) for patients reaching the primary composite

endpoint. For the following individual components of the primary endpoint, the results also

showed significant risk reduction in the group treated with losartan potassium as compared to

placebo: 25.3% risk reduction in doubling of serum creatinine (21.6% vs 26.0%), (p=0.006);

28.6% risk reduction in end-stage renal disease (19.6% vs 25.5%), (p=0.002). The rate of the all-

cause deaths component was not significantly different between losartan and placebo group,

21.0% and 20.3%, respectively.

The secondary endpoints of the study were: change in proteinuria; the rate of progression of

renal disease; and the composite of morbidity and mortality from cardiovascular causes

(hospitalization for heart failure, myocardial infarction, revascularization, stroke, hospitalization

for unstable angina, or cardiovascular death). For the secondary endpoint of change in

proteinuria, the results showed an average reduction of 34.3% in the level of proteinuria in the

group treated with losartan potassium (p<0.001) over the mean of 3.4 years. For the secondary

endpoint of rate of progression of renal disease, treatment with losartan potassium reduced the

rate of decline in renal function during the chronic phase of the study by 13.9%, (p=0.01) as

measured by the reciprocal of the serum creatinine concentration.

In this study, losartan potassium was generally well tolerated as evidenced by a similar incidence

of discontinuations due to side effects compared to placebo. A tertiary endpoint in the study was

assessment of quality of life. The results of this analysis suggest that there is no difference in the

change of quality of life between treatment arms.


Pediatric Indication

Study Demographics and Trial Design Table 7: Summary of Patient Demographics for Clinical Trials

Study No. Trial Design Dosage, Route of

Administration

and Duration

Study

Subjects

(n=number)

Mean Age

(Range)

Gender

227 A double-blind,

randomized dose-

response study of

losartan in children

with diastolic

hypertension

Oral administration

once daily

Losartan 2.5 mg,

25 mg, or 50 mg for

patients weighing

<50 kg

Losartan 5 mg,

50 mg, or 100 mg

for patients who

weigh ≥50 kg

Duration: 3 weeks

double-blind

treatment period

177 12

(6 to 16 years)

Male: 99

Female: 78

Study Results Table 8: Losartan Pediatric Dose-Response Study - Summary of Weight - Adjusted Dose Responses

(Intention-to-Treat Approach)

Dose N Day 1 Day 15 Day 22 Mean Change

(Day 15-Day 1)

(SD)

Mean Change

(Day 22-Day 1)

(SD)

95% CI for

Mean Change

(Day 22-Day 1)

Low

(2.5/5 mg)

70 87.92 80.80 81.91 -7.12 (6.47) -6.01 (7.61) -7.82, 4.19

Middle

(25/50 mg)

40 89.38 78.40 77.73 -10.98 (8.66) -11.65 (9.08) -14.55, -8.75

High

(50/100 mg)

64 88.80 78.56 76.59 -10.24 (9.14) -12.21 (8.86) -14.42, -10.00

N: Patients with both baseline (on Day 1) and post-dose measurements

SD: Standard Deviation

Mean Change: Measurement on day 15 (or 22) minus measurement on Day 1

CI: Confidence Interval

In a clinical study involving 177 hypertensive pediatric patients 6 to 16 years of age, patients

who weighed ≥20 kg to <50 kg received either 2.5, 25 or 50 mg of losartan daily and patients

who weighed ≥50 kg received either 5, 50 or 100 mg of losartan daily. Losartan administration

once daily lowered trough diastolic blood pressure in a dose-dependent manner. The dose

response to losartan was observed across all subgroups (e.g. age, tanner stage, gender, and race).

Evaluation of dose response based on the mean weight adjusted dose indicates that a starting

dose of losartan 0.75 mg/kg (up to 50 mg) once daily is appropriate. However, the lowest doses

studied, 2.5 mg and 5 mg, corresponding to an average daily dose of 0.07 mg/kg, did not appear

to offer consistent antihypertensive efficacy. In this study, losartan potassium up to an average

daily dose of 1.44 mg/kg (maximum 100 mg) once daily, is generally tolerated in hypertensive

children.


Overall, no significant differences in antihypertensive effect of losartan were detected when

patients were analyzed according to age (<, ≥ 12 years old) or gender. While blood pressure was

reduced in all racial groups examined, too few non-white patients were enrolled to compare the

dose-response of losartan in non-white subgroup.

LIFE Study

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) was a multicentre,

randomized, double-blind study comparing losartan potassium-and atenolol-based therapies in

9193 hypertensive patients with ECG-documented left ventricular hypertrophy (LVH). The

primary endpoint was a composite of cardiovascular death, nonfatal stroke, or nonfatal

myocardial infarction (MI). A 15% relative difference in the primary endpoint was selected to

demonstrate superiority between the treatment groups with 80% power. A primary event

occurred in 11% of the losartan potassium-based group and 13% of the atenolol-based group

yielding a relative difference of 13% (adjusted hazard ratio of 0.87 (CI 0.77, 0.98) and p=0.021).

The individual components of the primary composite endpoint did not consistently support the

overall result. The difference between the groups was primarily the result of an effect on stroke.

Treatment with losartan potassium reduced the risk of stroke by 25% relative to atenolol

(p=0.001) (see Figure 1 and Table 5). For the cardiovascular mortality component, there was a

non-significant trend in favour of the losartan potassium-based therapy, while for the myocardial

infarction component there was a non-significant difference in favour of atenolol-based

treatment. Although the LIFE study favoured losartan potassium over atenolol with respect to the

primary composite endpoint, corroborative results from a confirmatory study are not available. A

per-protocol analysis, which excluded patients with important protocol violations and censored

patients 14 days after permanently discontinuing study medications or 14 days after starting

prohibited therapy, showed that the primary endpoint was consistent but, did not reach statistical

significance (hazard ratio, 0.865, 95% CI 0.748, 1.002; p=0.053). The statistical power of the

per-protocol analysis was lower than for the intent-to-treat analysis because approximately one

third of the events were excluded.

Patients aged 55-80 years, with previously treated or untreated hypertension and ECG signs of

LVH were included in the study. According to NHANES III, the prevalence of LVH, established

by ECG, in patients with hypertension who are similar to the patients in the LIFE study is 12.8%

in White patients and 26.8% in Black patients in the general population. The following patients

were excluded: patients with secondary hypertension; myocardial infarction or stroke within the

previous six months; angina pectoris requiring treatment with β-blockers or calcium-antagonists;

heart failure or left ventricular ejection fraction of 40% or less; or a disorder that, in the treating

physician’s opinion, required treatment with losartan-based or another angiotensin-II type 1-

receptor antagonist, atenolol or another β-blocker, hydrochlorothiazide, or angiotensin-

converting-enzyme inhibitors. Patients were randomized to receive once daily losartan potassium

50 mg (n= 4605) or atenolol 50 mg (n= 4588). If goal blood pressure (<140/90 mmHg) was not

reached, hydrochlorothiazide (12.5 mg) was added first and, if needed, the dose of losartan

potassium or atenolol was then increased to 100 mg once daily. If necessary, other

antihypertensive treatments (e.g. increase in dose of hydrochlorothiazide therapy to 25 mg or

addition of other diuretic therapy, calcium-channel blockers, alpha-blockers, or centrally-acting

agents, but not ACE inhibitors, angiotensin II antagonists, or beta-blockers) were added to the

treatment regimen to reach the goal blood pressure.


Of the randomized 9193 patients, 54% were female and 6% were Black. The mean age was

67 years with 62% being 65 years or older. At baseline, 13% had diabetes, 14% had isolated

systolic hypertension, 16% had coronary heart disease, and 8% had cerebrovascular disease.

There were no significant differences in baseline demographics, clinical characteristics and

medical history between the two groups. Baseline mean blood pressure was 174/98 mmHg in

both treatment groups. The mean length of follow-up was 4.8 years. At the end of study or at the

last visit before a primary endpoint, 77% of the group treated with losartan potassium and 73%

of the group treated with atenolol were still taking study medication. Of the patients still taking

study medication, the mean doses of losartan potassium and atenolol were both about

80 mg/day, and 15% were taking atenolol or losartan as monotherapy, while 77% were also

receiving hydrochlorothiazide (at a mean dose of 20 mg/day in each group). Blood pressure

reduction measured at trough was similar for both treatment groups, but blood pressure was not

measured at any other time of the day. At the end of the study or at the last visit before a primary

endpoint, the average blood pressures were 144.1/81.3 mmHg for the group on losartan-based

therapy and 145.4/80.9 mmHg for the atenolol-based therapy patients. The difference in systolic

blood pressure of 1.3 mmHg was significant (p< 0.001), while the difference of 0.4 mmHg in

diastolic blood pressure was not significant (p=0.098).

The results obtained for the primary endpoint and its components are shown in Figure 1.

Figure 1. Kaplan-Meier estimates of the primary endpoint of time to cardiovascular death, nonfatal stroke, or

nonfatal myocardial infarction in the groups treated with losartan potassium and atenolol. The Risk Reduction is

adjusted for baseline Framingham risk score and level of electrocardiographic left ventricular hypertrophy.

Table 9 also shows the results obtained for the components of the primary endpoint and those for

the secondary endpoints. It can be seen that the primary endpoint reached statistical significance

almost entirely due to the stroke component.

Losartan Potassium


Table 9: LIFE Study–Primary Composite Endpoint and Components of Primary Composite Endpoint

Losartan-

Based

Therapy

(n=4605)

Atenolol-

Based

Therapy

(n=4588)

Relative

Risk

Reduction†

95% CI p-Value

Number of

events (%)

Number of

events (%)

Primary Composite Endpoint 508 (11) 588 (13) 13% 2% to 23% 0.021

Components of Primary Composite Endpoint (as a first event)

Stroke (nonfatal‡ ) 209 (4.5) 286 (6.2)

Myocardial infarction

(nonfatal‡ )

174 (3.8) 168 (3.7)

Cardiovascular mortality 125 (2.7) 134 (2.9)

Secondary Endpoints (any time in study)

Stroke (fatal/nonfatal) 232 (5) 309 (7) 25% 11% to 37% 0.001

Myocardial infarction

(fatal/nonfatal)

198 (4) 188 (4) -7% -13% to 12% 0.491

Cardiovascular mortality 204 (4) 234 (5) 11% -7% to 27% 0.206

Due to CHD 125 (3) 124 (3) -3% -32% to 20% 0.839

Due to Stroke 40 (1) 62 (1) 35% 4% to 67% 0.032

Other § 39 (1) 48 (1) 16% -28% to 45% 0.411

† Adjusted for baseline Framingham risk score and level of electrocardiographic left ventricular hypertrophy

‡ First report of an event, in some cases the patient died subsequently to the event reported

§ Death due to heart failure, non-coronary vascular disease, pulmonary embolism, or a cardiovascular cause other

than stroke or coronary heart disease

Although the LIFE study favoured losartan potassium-based therapy over atenolol-based therapy

with regards to stroke, it should be remembered that stroke was a secondary endpoint in the LIFE

study. A difference was observed between the two treatment groups in terms of the number of

patients with stroke who also had an atrial fibrillation: losartan potassium group (13.4%) and

atenolol group (20.5%).

Other clinical endpoints of the LIFE study were: total mortality, hospitalization for heart failure

or angina pectoris, coronary or peripheral revascularization procedures, and resuscitated cardiac

arrest. There were no significant differences in the rates of these endpoints between the losartan

potassium and atenolol groups.

In the Life study, Afro-American Black patients treated with atenolol-based treatment were at

lower risk of experiencing the primary composite endpoint compared with Afro-American Black

patients treated with losartan-based treatment. In the subgroup of Afro-American Black patients

(n=533), there were 29 primary endpoints among 263 patients on atenolol (11%, 26 per

1000 patient-years) and 46 primary endpoints among 270 patients (17%, 42 per 1000 patient-

years) on losartan potassium. This finding could not be explained on the basis of differences in

the populations other than race or on any imbalances between treatment groups. In addition,

blood pressure reductions in both treatment groups were consistent between Afro-American

Black and non-Black patients. Regarding stroke, the results favoured atenolol-based therapy in

Afro-American Blacks. The LIFE study provides no evidence that the benefits of losartan-based


treatment on reducing the risk of cardiovascular events in hypertensive patients with left

ventricular hypertrophy apply to Afro-American Black patients.

DETAILED PHARMACOLOGY

Following oral administration of losartan potassium to patients with mild to moderate alcoholic

cirrhosis, AUC of losartan and its active metabolite, E-3174, were about 5-times and 1.7-times

greater, respectively, than in young healthy male volunteers. Compared to these normal subjects,

the total plasma clearance of losartan in patients with hepatic insufficiency was about 50% lower

and the oral bioavailability was about 2-times higher.

In an 8-week controlled study of the incidence of cough in hypertensive patients with a history of

cough during ACE inhibitor therapy, the incidence of cough reported by patients receiving

losartan potassium or hydrochlorothiazide was similar and was significantly less than in patients

rechallenged with an ACE inhibitor. In addition, an overall analysis of double-blind clinical trials

in 4131 patients revealed that the incidence of spontaneously reported cough in patients treated

with losartan potassium monotherapy (n=2085; 3.1%) or losartan potassium plus

hydrochlorothiazide (n=858; 2.6%) was similar to that of patients treated with placebo (n=535;

2.6%) or hydrochlorothiazide alone (n=271; 4.1%), whereas the incidence with ACE inhibitors

(n=239) was 8.8%.

TOXICOLOGY

Acute Toxicity

The oral LD50 of losartan potassium in male mice is 2248 mg/kg (6744 mg/m2). Significant

lethality was observed in mice and rats after oral administration of 1000 mg/kg (3000 mg/m2)

and 2000 mg/kg (11800 mg/m2) respectively (see Table 10).

Table 10: Acute Toxicity

Route

Species

Sex

LD50 Values Maximum

Tolerated Dose

Intraperitoneal

Mouse

Rat

Female

Male

Female

Male

-

-

-

-

>160 mg/kg - < 400 mg/kg

>100 mg/kg - < 200 mg/kg

Intraperitoneal

study with

active metabolite,

E-3174 (L-158,641)

Mice

Female

441.3 mg/kg

-


Route

Species

Sex

LD50 Values Maximum

Tolerated Dose

Oral

Mouse

Rat

Dog

Female

Male

Female

Male

Female

Male

2248 mg/kg

-

-

-

-

500 mg/kg – 1000 mg/kg

~1000 mg/kg

>160 mg/kg - < 320 mg/kg

Chronic Toxicity

The toxic potential of losartan potassium was evaluated in a series of repeated dose oral toxicity

studies of up to three months in monkeys and up to one year in rats and dogs. There were no

findings that would preclude administration at the therapeutic dosage level (see Table 11).

Table 11: Chronic Toxicity

a) Oral Administration

Species Duration No. of

Animals/

Group

Dose

mg/kg/

day

Effects

Rat

[Sprague

-Dawley

Crl:CD

(SD) BR]

5 weeks

12 M + 12

F

0, 15, 45,

135

Mid- and high-dose males: slight decrease in body weight

gain.

High-dose males: slight decrease in red blood cell count.

Males all dosage levels: decrease in heart weight.

High-dose groups: slight increases in BUN; focal gastric

lesions.

Mid- and high-dose groups: slight increase in serum chloride.

All dosage levels: slight increases in serum glucose.

Rat

[Sprague

-Dawley

Crl:CD

(SD) BR]

14 weeks 17 M + 17

F

0, 15, 45,

135

Mid- and high-dose males: slight decreases in the rate of

body weight gain; increase in BUN; grossly evident focal

lesions in the gastric mucosa.

High-dose males: slight decreases in RBC parameters;

increase in cholesterol; alkalinization of the urine.

Males all dosage levels: decrease in heart weight.

High-dose females: increase in BUN.

High-dose groups: increase in sodium, chloride, and/or

potassium.

Rat

[Sprague

-Dawley

Crl:CD

(SD) BR]

53 weeks 30 M + 30

F

0, 15, 45,

135

High-dose males: slight decrease in erythrocyte parameters

(week 25); slight increase in serum phosphorus (week 25);

focal erosions of the glandular mucosa of the stomach (also

noted in one low-dose male).

Mid- and high-dose males: increases in BUN; decreased heart

weight and heart weight relative to brain weight (at terminal

necropsy); very slight hyperplasia of juxtaglomerular cells (at

interim necropsy).

High-dose females: increases in BUN; decreased absolute

heart weight and heart weight relative to brain weight (at

interim necropsy).

Mid- and high-dose females: slight decreases in food


Species Duration No. of

Animals/

Group

Dose

mg/kg/

day

Effects

consumption; slight decrease in erythrocyte parameters (high-

dose week 39, mid-dose weeks 39 and 51).

All females: decreases in serum triglycerides.

All groups: decreases in urinary protein; very slight

juxtaglomerular cell hyperplasia; lower incidence and severity

of spontaneous chronic nephritis.

Mid- and high-dose groups: postdose salivation (weeks 11

and 20).

High-dose groups: decrease in body weight gain.

Dog

(Beagle)

5 weeks 4 M + 4 F 0, 15,

45,135

All groups: adverse gastrointestinal effects (emesis, abnormal

stools, positive fecal occult blood).

No treatment-related mortality or change in body weight, food

consumption, urinalysis, serum biochemistry, or hematology

parameters. No treatment related postmortem findings.

Dog

(Beagle)

14 weeks 5 M + 5 F 0, 5,

25, 125

High-dose males: slight decrease in erythroid parameters.

High-dose groups: gastrointestinal toxicity (emesis, abnormal

stool colour and consistency, fecal occult blood); slight

decrease in heart weight.

Mid-dose groups: excessive salivation and emesis.

No treatment-related effects on body weight, food

consumption, clinical pathology, electrocardiography, physical

exams, ophthalmoscopic exams, or gross and microscopic

postmortem findings.

Dog

(Beagle)

53 weeks 8 M + 8 F 0, 5,

25, 125

High-dose groups: predose and/or postdose hypersalivation;

occasional emesis and change in stool consistency and colour.

Mid- and high-dose groups: sporadic, isolated increases in

serum ALT.

No treatment-related alteration in body weight or food

consumption, ophthalmologic findings or changes in

electrocardiographic, hematologic, or urinalysis parameters. No

treatment-related mortality.

Monkey

[Rhesus

(Macaca

mulatta)]

14 weeks 4 M + 4 F 0, 20, 100,

300

High-dose group: slight decrease in erythrocyte parameters

(weeks 8 and 11); slight decrease in BUN (week 11); increase

in angiotensin II levels (24 hours postdose); tarry intestinal

contents and small depressed, reddened foci in the stomach

and/or small intestine (at necropsy).

No treatment-related physical signs, mortality, or changes in

food consumption, body weight, ophthalmic exams, or

urinalysis.

No treatment-related changes in organ weights.


Table 11 - Chronic Toxicity (continued)

b) IV Administration

Species Duration No. of Animals/

Group

Dose

mg/kg/day

Effects

Rats

[Sprague-

Dawley

Crl:CD (SD)

BR]

16 days 15 M + 15 F

0, 0.92,

4.59, 9.17

High-dose males: slight decreases in erythrocyte count

and hematocrit.

No treatment-related deaths, clinical signs, or changes in

body weight gain, food consumption, ophthalmology,

serum biochemistry, or urinalysis.

Rats

[Sprague-

Dawley

Crl:CD (SD)

BR]

15 days 15 M + 15 F

0, 1, 5, 10†

Mid- and high-dose males: slight decrements in body

weight.

All groups: slight decrease in heart weight; slight

decrease in mean terminal body weight.

No treatment-related effects on food consumption,

ophthalmologic exams, hematology, serum biochemical

determinations, or urinalysis.

Dogs

(Beagle)

17 days 4 M + 4 F 0, 0.92,

4.59, 9.17

No drug-related deaths, no drug-related clinical signs, and

no drug-related changes in body weight gain, food

consumption, ophthalmology, electrocardiography,

hematology, serum biochemistry and urinalysis.

No treatment-related changes in organ weight or gross

microscopic changes.

Dogs

(Beagle)

15 days 4 M + 4 F 0, 1, 5, 10† No drug-related deaths, no drug-related clinical signs, and

no drug-related changes in body weight gain, food

consumption, ophthalmology, electrocardiography,

hematology, serum biochemistry and urinalysis.

No treatment-related changes in organ weight or gross

microscopic changes. † E-3174 (L-158,641): Primary pharmacologically active metabolite of losartan

Reproduction

Fertility and reproductive performance were not affected in male and female rats given oral

doses of losartan potassium up to approximately 150 and 300 mg/kg/day, respectively.

Teratology

Losartan potassium has been shown to produce adverse reactions in rat fetuses and neonates. The

reactions include decreased body weight, mortality and/or renal toxicity. Pharmacokinetic

evaluation of fetal plasma showed significant levels of losartan and its active metabolite, E-3174

(L-158,641), on Gestation Day 20 compared to negligible value on Gestation Day 15. In

addition, significant levels of losartan and its active metabolite were shown to be present in rat

milk. Based on these findings, the fetal and neonatal effects of losartan potassium in rats are

attributed to drug exposure in late gestation and during lactation.


Carcinogenesis

Losartan potassium was not carcinogenic when administered at maximum tolerated dosage levels

to rats and mice for 105 weeks (maximum dose of 270 mg/kg/day) and 92 weeks (maximum

dose of 200 mg/kg/day), respectively.

Mutagenesis

Losartan potassium was negative in the microbial mutagenesis and V-79 mammalian cell

mutagenesis assays. In addition, there was no evidence of direct genotoxicity in the in vitro

alkaline elution and in vitro chromosomal aberration assays. Similarly, there was no induction of

chromosomal aberrations in bone marrow cells of male or female mice after the administration of

toxic oral doses of up to 1500 mg/kg (4500 mg/m2). In addition, the active metabolite showed no

evidence of genotoxicity in the microbial mutagenesis, in vitro alkaline elution, and in vitro

chromosomal aberration assays.


REFERENCES

1. Brenner BM, Cooper ME, DeZeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G,

Snappin SM, Zhang Z, Shahinfar S, for the RENAAL Study Investigators. Effects of

Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and

Nephropathy. N Engl J Med 2001; 345:861-9.

2. Chan JCN, Critchley JAJH, Lappe JT, Raskin SJ, Snavely D, Goldberg AI, Sweet CS.

Randomised, Double-blind, Parallel study of the Anti-hypertensive Efficacy and Safety

of Losartan Potassium Compared with Felodipine ER in Elderly Patients with Mild to

Moderate Hypertension. J Human Hypertens 1995;9:765-71.

3. Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, Fyhrquist F, Ibsen

H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P,

Oparil S, Wedel H, for the LIFE study group. Cardiovascular Morbidity and Mortality in

the Losartan Intervention for Endpoint Reduction in Hypertension Study (LIFE): a

randomized trial against atenolol. The Lancet 2002;359(9311):995-1003.

4. Dahlöf B, Keller SE, Makris L, Goldberg AI, Sweet CS, Lim NY. Efficacy and

Tolerability of Losartan Potassium and Atenolol in Patients with Mild to Moderate

Essential Hypertension. Am J Hypertens 1995;8:578-83.

5. Eberhardt RT, Kevak RM, Kang PM, Frishman WH. Angiotensin II Receptor Blockade:

An Innovative Approach to Cardiovascular Pharmacotherapy. J Clin Pharmacol

1993;33(11):1023-38.

6. Ellis D. et al. Antihypertensive and Renoprotective Efficacy and Safety of Losartan; AJH

2004; 17:928-935.

7. Goldberg AI, Dunlay MC, Sweet CS. Safety and Tolerability of Losartan Potassium, an

Angiotensin II Receptor Antagonist, Compared With Hydrochlorothiazide, Atenolol,

Felodipine ER, and Angiotensin-Converting Enzyme Inhibitors for the Treatment of

Systemic Hypertension. Am J Cardiol 1995;75:793-5.

8. Goldberg M, Tanaka W, Barchowsky A, Bradstreet T, McCrea J, Lo MW, McWilliams

E, Bjornsson T. Effects of Losartan on Blood Pressure, Plasma Renin Activity, and

Angiotensin Il in Volunteers. Hypertension 1993;21:704-13.

9. Julius S, Alderman MH, Beevers G, Dahlof B, Devereux RB, Douglas JG, Edelman JM,

Harris KE, Kjeldsen SE, Nesbitt S, Randall OS, Wright JT Jr. Cardiovascular risk

reduction in hypertensive black patients with left ventricular hypertrophy: the LIFE

study, J AM Coll Cardiol 2004 Mar 17;43(6):1047-55.


10. Lacourcière Y, Brunner H, Irwin R, Karlberg BE, Ramsay LE, Snavely DB, Dobbins

TW, Faison EP, Nelson EB, the Losartan Cough Study Group. Effects of modulators of

the renin angiotensin-aldosterone system on cough. J Hypertens 1994;12(12):1387-93.

11. Ohtawa M, Takayama F, Saitoh K, Yoshinaga T, Nakashima M. Pharmacokinetics and

Biochemical Efficacy After Single and Multiple Oral Administration of Losartan, An

Orally Active Nonpeptide Angiotensin II Receptor Antagonist, In Humans. Br J Clin

Pharmacol 1993;35:290-7.

12. Shahinfar Sh.et al. A Double-Blind, Dose-Response Study of Losartan in Hypertensive

Children, 1 AJH 2005; 18:183-190.

13. Weber MA, Byyny RL, Pratt JH, Faison EP, Snavely DB, Goldberg AI, Nelson EB.

Blood Pressure Effects of the Angiotensin II Receptor Blocker, Losartan. Arch Intern

Med 1995;155:405-11.

14. Merck Canada Inc, PrCozaar® Product Monograph. Control no. 215619, Revision date:

September 17, 2018.

IMPORTANT: PLEASE READ


PART III: CONSUMER INFORMATION

Pr SANDOZ LOSARTAN


Read this carefully before you start taking Sandoz Losartan

and each time you get a refill. This leaflet is a summary and

will not tell you everything about Sandoz Losartan. Talk to

your doctor, nurse or pharmacist about your medical

condition and treatment and ask if there is any new

information about Sandoz Losartan.

ABOUT THIS MEDICATION

What the medication is used for:

Adults

Sandoz Losartan lowers high blood pressure;

Sandoz Losartan provides kidney protection by delaying

the worsening of kidney disease in type 2 diabetic

patients with protein in the urine (proteinuria) and high

blood pressure.

Children (6-16 years)

Sandoz Losartan lowers high blood pressure.

What it does:

Sandoz Losartan is an angiotensin receptor blocker (ARB).

You can recognize an ARB because its medicinal

ingredient ends in ‘‘-SARTAN’’. It lowers blood pressure.

This medicine does not cure high blood pressure. It helps to

control it. Therefore, it is important to continue taking

Sandoz Losartan regularly even if you feel fine.

When it should not be used:

Do not take Sandoz Losartan if you:

are allergic to losartan potassium or any of the

nonmedicinal ingredients in the formulation.

have difficulty urinating or produce no urine.

are already taking a blood pressure-lowering medicine that

contains aliskiren (such as Rasilez) and you have diabetes

or kidney disease.

What the medicinal ingredient is:

Losartan potassium

What the nonmedicinal ingredients are:

colloidal anhydrous silica, hydroxypropyl cellulose,

hypromellose, lactose monohydrate, macrogol 400,

magnesium stearate, microcrystalline cellulose,

pregelatinized starch, talc and colouring agents (titanium

dioxide).

Sandoz Losartan 25 mg, 50 mg and 100 mg tablets contain

the following amounts of potassium: 2.12 mg (<1 mmol),

4.24 mg (<1 mmol), and 8.48 mg (<1 mmol) respectively.

Although Sandoz Losartan tablets contain potassium, this

amount is too small to replace potassium supplements. If

your physician has prescribed potassium supplements,

continue to follow their advice.

What dosage forms it comes in:

Tablets of 25 mg, 50 mg and 100 mg.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions - Pregnancy

Sandoz Losartan should not be used during

pregnancy. If you discover that you are pregnant

while taking Sandoz Losartan, stop the medication

and contact your doctor, nurse or pharmacist as

soon as possible.

BEFORE you use Sandoz Losartan talk to your doctor, nurse

or pharmacist if you:

are allergic to any drug.

have experienced an allergic reaction ( angioedema) with

swelling of the hands, feet, or ankles, face, lips, tongue,

throat, or sudden difficulty breathing or swallowing to any

drug that blocks the renin-angiotensin renin system (ACEi,

ARB, renin inhibitors). Be sure to tell your doctor, nurse, or

pharmacist that this has happened to you.

have narrowing of an artery or a heart valve.

have had a heart attack or stroke.

are taking a salt substitute that contains potassium,

potassium supplements, or a potassium-sparing diuretic ( a

specific kind of ‘‘water pill’’ that makes your body keep

potassium).

are on a low salt diet.

are less than 18 years old.

are taking a medicine that contains aliskiren, such as

Rasilez, used to lower high blood pressure. The

combination with Sandoz Losartan is not recommended.

are taking an angiotensin-converting-enzyme inhibitor

(ACE). You can recognize ACE inhibitors because their

medicinal ingredient ends in ‘‘-PRIL’’.

are on dialysis.

are taking any medication including non-prescription and

herbal products.

are dehydrated or suffer from excessive vomiting, diarrhea

or sweating.

have heart failure.

have diabetes, liver or kidney disease.

have to undergo any kind of surgery and general anesthesia

(even at the dentist’s office). Tell the physician or dentist

that you are taking Sandoz Losartan, as there may be a

sudden fall in blood pressure associated with general

anasthesia.



are allergic to this drug or to any ingredient in the

formulation .

are taking other drugs that may increase serum potassium

(e.g. trimethoprim-containing products).

You may become sensitive to the sun while taking Sandoz

Losartan. Exposure to sunlight should be minimized until you

know how you respond.

Driving and using machines: Before doing tasks which

require special attention, wait until you know how you respond

to Sandoz Losartan. Being dizzy, lightheaded, or fainting can

occur. Take care especially after the first dose and when the

dose is increased.

You are pregnant, breast-feeding or thinking of becoming

pregnant?

Taking Sandoz Losartan during pregnancy can cause injury and

even death to your baby. This medicine should not be used

during pregnancy. If you are planning to become pregnant

while taking Sandoz Losartan, contact your doctor, nurse or

pharmacist immediately.

It is possible that Sandoz Losartan passes into breast milk. You

should discuss with your physician about taking Sandoz

Losartan while breastfeeding.

INTERACTIONS WITH THIS MEDICATION

As with most medicines, interactions with other drugs are

possible. Tell your doctor, nurse or pharmacist about all the

medicines you take, including drugs prescribed by other

doctors, vitamins, minerals, natural supplements, or alternative

medicines.

The following may interact with Sandoz Losartan:

Digoxin, a heart medication.

Lithium used to treat bipolar disease.

Nonsteroidal anti-inflammatory drugs (NSAIDs), used to

reduce pain and swelling. Examples include ibuprofen,

naproxen, and celecoxib.

Other blood pressure lowering drugs, including diuretics

(‘‘water pills’’), aliskiren-containing products (e.g.

Rasilez), or angiotensin converting enzyme (ACE)

inhibitors. When taken in combination with Sandoz

Losartan, they may cause excessively low blood pressure.

Warfarin used to thin the blood and prevent blood clots.

Antibiotics used to treat bacterial infections, such as

Rifampin and erythromycin.

Fluconazole, used to treat fungal infections.

Phenobarbital, used to treat epilepsy.

Cimetidine, used to treat heartburn and stomach ulcers.

Agents increasing serum potassium, such as potassium

supplements, salt substitutes containing potassium, a

potassium-sparing diuretic (a specific kind of ‘‘water

pill’’) or other drugs that may increase serum potassium

(e.g., trimethoprim-containing products).

PROPER USE OF THIS MEDICATION

Take Sandoz Losartan exactly as prescribed. It is

recommended to take your dose at about the same time

every day.

Usual dose:

Take Sandoz Losartan every day exactly as your

doctor has instructed. It is important to continue taking

Sandoz Losartan for as long as your doctor prescribes it in

order to maintain smooth control of your blood pressure.

Sandoz Losartan may be taken with or without food,

but it should be taken consistently with respect to food

intake, at about the same time every day.

High blood pressure:

Adults:

For adult patients, the usual starting dose is 50 mg once

daily. The usual dose range is 50 to 100 mg once daily.

Most older patients require the same dose as younger

patients, since Sandoz Losartan works equally well and is

equally well tolerated by most older and younger adult

patients.

Children (6 - 16 years):

For pediatric patients (6-16 years of age) who can swallow

tablets, the recommended dose is 25 mg once daily in

patients between 20 and 49 kg. The dose can be increased

to a maximum of 50 mg once daily. In patients greater or

equal to 50 kg, the starting dose is 50 mg once daily. The

dose can be increased to a maximum of 100 mg once

daily.

Type 2 diabetes patients with protein in the urine and high

blood pressure:

Adults

For adults, the usual starting dose is 50 mg once daily. The

dose may be increased to 100 mg once daily.

Overdose:

If you think you have taken too much Sandoz Losartan, contact

your doctor, nurse, pharmacist, hospital emergency department

or regional Poison Control Centre, immediately even if there

are no symptoms.

Missed dose:

If you have forgotten to take your dose during the day, carry on

with the next one at the usual time. Do not double dose.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Any medicine may have unintended or undesirable effects, so-

called side effects. Tell your physician or pharmacist promptly

about these or any other unusual symptoms.

Side effects may include:

Dizziness



Fatigue

Rash

Diarrhea, vomiting

Change in taste

Headache

Back or leg pain, muscle cramps

Some patients, especially those with type 2 diabetes with

protein in the urine, may also develop increased levels of

potassium in their blood.

If any of these affects you severely, tell your doctor, nurse

or pharmacist.

Sandoz Losartan can cause abnormal blood test results. Your

doctor will decide when to perform blood tests and will

interpret the results.

This is not a complete list of side effects. For any unexpected

effects while taking Sandoz Losartan, contact your doctor,

nurse or pharmacist.

HOW TO STORE IT

Bottles: Store Sandoz Losartan between 15 and 30°C. Keep

container tightly closed. Protect from light.

Blisters: Store Sandoz Losartan between 15 and 30°C.

Keep all medicines out of the reach and sight of children.

REPORTING SIDE EFFECTS

You can report any suspected side effects associated with the use

of health products to Health Canada by:

Visiting the Web page on Adverse Reaction Reporting

(https://www.canada.ca/en/health- canada/services/drugs-

health-products/medeffect-canada/adverse-reaction-

reporting.html) for information on how to report online, by

mail or by fax; or

Calling toll-free at 1-866-234-2345.

NOTE: Contact your health professional if you need information

about how to manage your side effects. The Canada Vigilance

Program does not provide medical advice.

MORE INFORMATION

If you want more information about Sandoz Losartan:

Talk to your healthcare professional

Find the full Product Monograph that is prepared for

healthcare professionals and includes this Consumer

Information by visiting the Health Canada Website

www.canada.ca/en/health-canada or Sandoz Canada

Inc. web site www.sandoz.ca or by calling Sandoz

Canada Inc. at 1-800-361-3062

or by written request at:

110, Rue de Lauzon

Boucherville, (QC), Canada

J4B 1E6

or by e-mail at:

[email protected]

This leaflet was prepared by Sandoz Canada Inc.

Last revised: November 13, 2018

SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN

AND WHAT TO DO ABOUT THEM

Symptom/effect Talk with

your doctor,

nurse or

pharmacist

Stop

taking

drug and

seek

immediate

medical

help

Only

if

severe

In all

cases

Common

Low Blood Pressure: dizziness,

fainting, lightheadedness

Increased levels of potassium in the

blood: irregular heartbeats, muscle

weakness and generally feeling

unwell

Uncommon

Allergic reaction: rash, hives,

swelling of the face, lips, throat or

tongue, difficulty breathing or

swallowing

Kidney Disorder: change in

frequency of urination, nausea,

vomiting, swelling of extremities,

fatigue

Liver Disorder: yellowing of the skin

or eyes, dark urine, abdominal pain,

nausea, vomiting, loss of appetite

Rare

Rhabdomyolysis: muscle pain that

you cannot explain, muscle tenderness

or weakness, dark brown urine

Very rare

Decreased Platelets: bruising,

bleeding, fatigue and weakness

https://www.canada.ca/en/health-%20canada/services/drugs-health-products/medeffect-canada/adverse-reaction-reporting.html



http://www.canada.ca/en/health-canada

http://www.sandoz.ca/

Documents

PRODUCT MONOGRAPH - Sandoz Canada · Sandoz Losartan may be used alone or concomitantly with thiazide diuretics. A great majority of patients with severe hypertension in controlled